The present invention relates to novel triazolo derivatives, pharmaceutically acceptable salts thereof, chemokine inhibitors, particularly CC chemokine inhibitors, containing the same as effective components.
It is well-known that in many inflammatory diseases, infiltration of leukocytes such as macrophages, neutrophils, eosinophils and lymphocytes into the inflammatory site is observed. It is thought that a physiologically active substance called chemotactic factor plays a role in the tissue accumulation of leukocytes. In particular, it has been reported that chemokines known as chemotactic cytokines induce not only infiltration of leukocytes, but also degranulation of leukocytes, production of active oxygen and adhesion reaction, and play central roles in the chemotaxis and activation of leukocytes (e.g., The New England Journal of Medicine, Vol. 338, pp. 436-445, 1998).
Chemokines are classified into 4 subgroups, i.e., C chemokines, CC chemokines, CXC chemokines and CXXXC chemokines, depending on the characteristics of the amino acid sequences (e.g., Blood, Vol. 90, pp. 909-928, 1997).
It is known that lymphotactins, to which C chemokines belong have chemotactic activities to T lymphocytes, while CC chemokines induce chemotactic activities to leukocytes other than nuetrophils, such as monocytes, lymphocytes, eosinophils, basophils and NK cells. CXC chemokines have chemotactic activities mainly to neutrophils and CXXC chemokines have chemotactic activities mainly to NK cells (e.g., The New England Journal of Medicine, Vol. 338, pp. 436-445, 1998). Such a cell specificity suggests that among these subgroups of chemokines, CC chemokines play important roles in the diseases including allergic diseases such as bronchial asthma and atopic dermatitis, chronic rheumatoid arthritis, sarcoidosis, pulmonary fibrosis, bacterial pneumonia, nephritis, atherosclerosis, ulcerative colitis, psoriasis, viral meningitis and AIDS. For example, in mice in which MIP-1xcex1, one of the CC chemokines, is knocked out, the pneumonia induced by infection with influenza virus is reduced (Science, Vol. 269, pp. 1583-1585, 1995). In addition, it is known that in mice in which CCR1, one of the receptors of CC chemokines, is knocked out, the response by helper T cells type 2 which give important contribute to onset of atopic diseases is reduced (The Journal of Experimental Medicine, Vol. 185, pp. 1959-1968, 1997), and that in mice in which CCR2 is knocked out, delayed hypersensitivity reaction and response by helper T cells type 1 is reduced (The Journal of Clinical Investigation, Vol. 100, pp. 2552-2561, 1997). Further, it is known that in mice in which eotaxin, one of CC chemokines, is knocked out, tissue accumulation of eosinophils, which play important roles as effector cells in allergic diseases, occurs (The Journal of Experimental Medicine, Vol. 185, pp. 785-790, 1997). Further, it has been reported that CCR5 and CCR3, which are CC chemokine receptors, are cofactors in infection of AIDS virus, and that RANTES, MIP-1xcex1 and MIP-1xcex2, which are CC chemokines prevent infection of AIDS virus (e.g., Annual Review of Immunology, Vol. 15, pp. 675-705, 1997).
Thus, drugs which inhibit activities of such chemokines are expected to be useful as prophylactic or therapeutic agents against these diseases. So far, 10 types of CC chemokine receptors (CCR), i.e., CCR1 to CCR10 are known (e.g., The New England Journal of Medicine, Vol. 338, pp. 436-445, 1998; and DNA and Cell Biology, Vol. 10, pp. 1249-1256, 1997). As for low molecular weight compounds which act on these receptors, although an inhibitor against CCR1 has been reported (e.g., Japanese Laid-open Patent Application (Kokai) No. 9-249566), low molecular weight compounds against other receptors as well as application thereof to therapeutic agents have not been reported.
An object of the present invention is to discover a substance which inhibits the actions of CC chemokines, thereby enabling prophylaxis and therapy of inflammatory diseases caused by infiltration by leukocytes such as monocytes, lymphocytes, acidophils, basophils and NK cells.
The present inventors intensively studied to discover that specific novel triazolo derivatives and pharmaceutically acceptable salts thereof have activities to inhibit actions of CC chemokines, thereby completing the present invention.
That is, the present invention provides a triazolo derivative of the Formula I: 
(wherein W represents a carbon atom or a nitrogen atom, X represents a C2-C6 straight chain alkyl group, a C3-C8 branched alkyl group, a C2-C6 fluoroalkyl group,
Formula II: 
(wherein m and n represent integers of 0 to 6, and xe2x80x94(CH2)nxe2x80x94 is bound to the position of any one of 2-, 3- and 4-position in the cyclohexane ring)
or Formula III: 
(wherein m and n represent integers of 0 to 6, and xe2x80x94(CH2)nxe2x80x94 is bound to the position of any one of 2-, 3- and 4-position in the benzene ring);
Y represents a carbon atom or a nitrogen atom; ... represents a single bond or a double bond; Z1 and Z2, which may or may not simultaneously exist, each represents C6-C18 substituted or non-substituted cyclohexyl group, indole-3-yl group, imidazoyl group, furyl group, thienyl group, pyrrolyl group, pyridyl group or QCR6R7R8, with the proviso that in cases where Z1 and Z2 represent QCR6R7R8, Q and R6 may or may not exist, and when Q exists, Q is selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom; and when R6 exists, R6 represents hydrogen or hydroxyl group; R7 and R8, which may be the sane or different, represent hydrogen, C1-C6 straight alkyl group, C3-C8 branched alkyl group, or one selected from the group consisting of C6-C16 substituted or non-substituted phenyl group, C10-C16 substituted or non-substituted naphthyl group and C6-C16 substituted or non-substituted cycloalkyl group, which phenyl group, naphthyl group or cycloalkyl group is bound through C0-C6 methylene chain; V represents a carbon atom or a nitrogen atom; R1 represents C1-C6 straight alkyl group or aryl group; R2 and R3, which may or may not exist and which may be the same or different, each is selected from the group consisting of C1-C6 straight alkyl group, C1-C6 straight alkoxyl group, C3-C8 branched alkyl group, C3-C8 branched alkoxyl group, hydroxyl group; chloro, bromo, fluoro, amino group, monoalkylamino group in which the alkyl group has 1 to 6 carbon atoms, diaikylamino group in which each alkyl group has 2 to 6 carbon atoms, trifluoromethyl group, and nitro group; in cases where V and W are carbon atoms and where V and W are bound through double bond, R4 does not exist, and R5 represents hydrogen, C1-C6 straight alkyl group, C1-C6 straight alkoxyl group, C3-C8 branched alkyl group, C3-C8 branched alkoxyl group, or represents one selected from the group consisting of C6-C16 substituted or non-substituted phenyl group, C10-C16 substituted or non-substituted naphthyl group and C6-C16 substituted or non-substituted cycloalkyl group, which phenyl group, naphthyl group or cycloalkyl group is bound through C0-C6 methylene chain; in cases where V is nitrogen atom and W is carbon atom and where V and W are bound through double bond, both R4 and R5 do not exist; in cases where V is carbon atom, W is nitrogen atom or carbon atom, and V and W are bound through single bond, R4 and R5 cooperatively represent oxo group; wherein the substituent(s) in said substituted phenyl group, substituted naphthyl group and substituted cycloalkyl group is(are) 1 to 5 C1-C6 straight alkyl group(s), C3-C6 branched alkyl group(s), phenyl group(s), phenoxy group(s), naphthyl group(s), cyclopentyl group(s) or cyclohexyl group(s)) or a pharmaceutically acceptable salt thereof. The present invention also provides a chemokine inhibitor comprising the above-described triazolo derivative of the present invention or a pharmaceutically acceptable salt thereof as an effective component.
The triazolo derivatives and pharmaceutically acceptable salts thereof according to the present invention inhibit actions of chemokines, particularly CC chemokines, of which actions are mediated by chemokine receptors such as CCR1, CCR2, CCR3 and the like. Therefore, the triazolo derivatives and pharmaceutically acceptable salts thereof according to the present invention are useful as therapeutic agents for allergic diseases such as bronchial asthma and atopic dermatitis, therapeutic agents for inflammatory diseases such as chronic rheumatoid arthritis, autoimmune diseases such as nephritis and ulcerative colitis, and as anti-AIDS drugs, and useful for prophylaxis and therapy of various diseases other than those mentioned above, in which chemokines are thought to participate.
As mentioned above, the triazolo derivatives according to the present invention are represented by the above-described Formula I. In Formula I, W represents a carbon atom or a nitrogen atom. X represents C2-C6 straight alkyl group which is ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl group; C3-C8 branched alkyl group such as 1-methylethyl, 2-methylethyl, 1,1-dimethylethyl, 1,2-dimethylethyl, 2,2-dimethylethyl, 1-methylpropyl, 2-methylpropyl, 3-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3,3-dimethylpropyl, 1,2-dimethylpropyl, 1,3-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 2,4-dimethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylpentyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 5,5-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,5-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,5-dimethylpentyl, 3,4-dimethylpentyl, 3,5-dimethylpentyl, 4,5-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 5,5-dimethylhexyl, 6,6-dimethylhexyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 1,4-dimethylhexyl, 1,5-dimethylhexyl, 1,6-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,6-dimethylhexyl, 3,4-dimethylhexyl, 3,5-dimethylhexyl, 3,6-dimethylhexyl, 4,5-dimethylhexyl and 5,6-dimethylhexyl; C2-C6 fluoroalkyl group such as 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 1-fluorobutyl,2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl, 1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl, 4,4-difluorobutyl, 1,2-difluorobutyl, 1,3-difluorobutyl, 1,4-difluorobutyl, 2,3-difluorobutyl, 2,4-difluorobutyl, 1-fluorohexyl, 2-fluorohexyl, 3-fluorohexyl, 4-fluorohexyl, 5-fluorohexyl, 5-fluorohexyl, 1,1-difluorohexyl, 2,2-difluorohexyl, 3,3-difluorohexyl, 4,4-difluorohexyl, 5,5-difluorohexyl, 6,6-difluorohexyl, 1,2-difluorohexyl, 1,3-difluorohexyl, 1,4-difluorohexyl, 1,5-difluorohexyl, 1,6-difluorohexyl, 2,3-difluorohexyl, 2,4-difluorohexyl, 2,5-difluorohexyl, 2,6-difluorohexyl, 3,4-difluorohexyl, 3,5-difluorohexyl, 3,6-difluorohexyl, 4,5-difluorohexyl, 4,6-difluorohexyl and 5,6-difluorohexyl groups; Formula II: 
(wherein m and n represent integers of 0 to 6, and xe2x80x94(CH2)nxe2x80x94 is bound to the position of any one of 2-, 3- and 4-position in the cyclohexane ring)
or Formula III: 
(wherein m and n represent integers of 0 to 6, and xe2x80x94(CH2)nxe2x80x94 is bound to the position of any one of 2-, 3- and 4-position in the benzene ring).
Y represents a carbon atom or a nitrogen atom; ... represents single bond or double bond; Z1 and Z2, which may or may not exist simultaneously, each represents C6-C18 substituted or non-substituted cyclohexyl group such as cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,2-dimethylcyclohexyl, 3,3-dimethylcyclohexyl, 4,4-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2-phenylcyclohexyl, 3-phenylcyclohexyl, 4-phenylcyclohexyl, 2-naphthylcyclohexyl, 3-naphthylcyclohexyl, 4-naphthylcyclohexyl, 2-phenylcyclohexyl, 3-phenoxycyclohexyl and 4phenoxycyclohexyl groups; indole-3-yl group; imidazoyl group; furyl group; thienyl group; pyrrolyl group; pyridyl group; or QCR6R7R8, with the proviso that in cases where Z1 and Z2 represent QCR6R7R8, Q and R6 may or may not exist, and when Q exists, Q is selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom; and when R6 exists, R6 represents hydrogen or hydroxyl group; R7 and R8 represent, which may be the same or different, represent hydrogen, C1-C6 straight alkyl group which is methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl group; C3-C8 branched alkyl group such as 1-methylethyl, 2methylethyl, 1,1-dimethylethyl, 1,2-dimethylethyl, 2,2-dimethylethyl, 1-methylpropyl, 2-methylpropyl, 3-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3,3-dimethylpropyl, 1,2-dimethylpropyl, 1,3-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 2,4-dimethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylpentyl, 1,1-dimethylpentyl 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 5,5-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,5-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,5-dimethylpentyl, 3,4-dimethylpentyl, 3,5-dimethylpentyl, 4,5-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 5,5-dimethylhexyl, 6,6-dimethylhexyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 1,4-dimethylhexyl, 1,5-dimethylhexyl, 1,6-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,6-dimethylhexyl, 3,4-dimethylhexyl, 3,5-dimethylhexyl, 3,6-dimethylhexyl, 4,5-dimethylhexyl and 5,6-dimethylhexyl groups; C6-C16 substituted or non-substituted phenyl group bound through C0-C6 methylene chain, such as phenyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, 2-methylphenyl, 2-methylbenzyl, 2-(2-methylphenyl)ethyl, 3-(2-methylphenyl)propyl, 4-(2-methylphenyl)butyl, 5-(2-methylphenyl)pentyl, 6-(2-methylphenyl)hexyl, 3-methylphenyl, 3-methylbenzyl, 2-(3-methylphenyl)ethyl, 4-(3-methylphenyl)propyl, 4-(3-methylphenyl)butyl, 5-(3-methylphenyl)pentyl, 6-(3-methylphenyl)hexyl, 4-methylphenyl, 4-methylbenzyl, 2-(4-methylphenyl)ethyl, 3-(4-methylphenyl)propyl, 4-(4-methylphenyl)butyl, 5-(4-methylphenyl)pentyl, 6-(4-methylphenyl)hexyl, 2-propylphenyl, 2-propylbenzyl, 2-(2-propylphenyl)ethyl, 3-(2-propylphenyl)propyl, 4-(2-propylphenyl)butyl, 5-(2-propylphenyl)pentyl, 6-(2-propylphenyl)hexyl, 3-propylphenyl, 3-propylbenzyl, 2-(3-propylphenyl)ethyl, 3-(3-propylphenyl)propyl, 4-(3-propylphenyl)butyl, 5-(3-propylphenyl)pentyl, 6-(3-propylphenyl)hexyl, 4-propylphenyl, 4-propylbenzyl, 2-(4-propylphenyl)ethyl, 3-(4-propylphenyl)propyl, 4-(4-propylphenyl)butyl, 5-(4-propylphenyl)pentyl, 6-(4-propylphenyl)hexyl, 2-cyclopentylphenyl, 2-cyclopentylbenzyl, 2-(2-cyclopentylphenyl)ethyl, 3-(2-cyclopentylphenyl)propyl, 4-(2-cyclopentylphenyl)butyl, 5-(2-cyclopentylphenyl)pentyl, 6-(2-cyclopentylphenyl)hexyl, 3-cyclopentylphenyl, 3-cyclopentylbenzyl, 2-(3-cyclopentylphenyl)ethyl, 3-(3-cyclopentylphenyl)propyl, 4-(3-cyclopentylphenyl)butyl, 5-(3-cyclopentylphenyl)pentyl, 6-(3-cyclopentylphenyl)hexyl, 4-cyclopentylphenyl, 4-cyclopentylbenzyl, 2-(4-cyclopentylphenyl)ethyl, 3-(4-cyclopentylphenyl)propyl, 4-(4-cyclopentylphenyl)butyl, 5-(4-cyclopentylphenyl)pentyl, 6-(4-cyclopentylphenyl)hexyl, 2-cyclohexylphenyl, 2-cyclohexylbenzyl, 2-(2-cyclohexylphenyl)ethyl, 3-(2-cyclohexylphenyl)propyl, 4-(2-cyclohexylphenyl)butyl, 5-(2-cyclohexylphenyl)pentyl, 6-(2-cyclohexylphenyl)hexyl, 3-cyclohexylphenyl, 3-cyclohexylbenzyl, 2-(3-cyclohexylphenyl)ethyl, 3-(3-cyclohexylphenyl)propyl, 4-(3-cyclohexylphenyl)butyl, 5-(3-cyclohexylphenyl)pentyl, 6-(3-cyclohexylphenyl)hexyl, 4-cyclohexylphenyl, 4-cyclohexylbenzyl, 2-(4-cyclohexylphenyl)ethyl, 3-(4-cyclohexylphenyl)propyl, 4-(4-cyclohexylphenyl)butyl, 5-(4-cyclohexylphenyl)pentyl, 6-(4-cyclohexylphenyl)hexyl, 2-phenyl-phenyl, 2-phenyl-benzyl, 2-(2-phenyl-phenyl)ethyl, 3-(2-phenyl-phenyl)propyl, 4-(2-phenyl-phenyl)butyl, 5-(2-phenyl-phenyl)pentyl, 6-(2-phenyl-phenyl)hexyl, 3-phenyl-phenyl, 3-phenyl-benzyl, 2-(3-phenyl-phenyl)ethyl, 3-(3-phenyl-phenyl)propyl, 4-(3-phenyl-phenyl)butyl, 5-(3-phenyl-phenyl)pentyl, 6-(3-phenyl-phenyl)hexyl, 4-phenyl-phenyl, 4-phenyl-benzyl, 2-(4-phenyl-phenyl)ethyl, 3-(4-phenyl-phenyl)propyl, 4-(4-phenyl-phenyl)butyl, 5-(4-phenyl-phenyl)pentyl, 6-(4-phenyl-phenyl)hexyl, 2-phenoxy-phenyl, 2-phenoxy-benzyl, 2-(2-phenoxy-phenyl)ethyl, 3-(2-phenoxy-phenyl)propyl, 4-(2-phenoxy-phenyl)butyl, 5-(2-phenoxy-phenyl)pentyl, 6-(2-phenoxy-phenyl)hexyl, 3-phenoxy-phenyl, 3-phenoxy-benzyl, 2-(3-phenoxy-phenyl)ethyl, 3-(3-phenoxy-phenyl)propyl, 4-(3-phenoxy-phenyl)butyl, 5-(3-phenoxy-phenyl)pentyl, 6-(3-phenoxy-phenyl)hexyl, 4-phenoxy-phenyl, 4-phenoxy-benzyl, 2-(4-phenoxy-phenyl)ethyl, 3-(4-phenoxy-phenyl)propyl, 4-(4-phenoxy-phenyl)butyl, 5-(4-phenoxy-phenyl)pentyl and 6-(4-phenoxy-phenyl)hexyl groups; C10-C16 substituted or non-substituted naphthyl group bound through C0-C6 methylene chain, such as naphthyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, 2-methylnaphthyl, 2-methylnaphthylmethyl, 2-(2-methylnaphthyl)ethyl, 3-(2-methylnaphthyl)propyl, 4-(2-methylnaphthyl)butyl, 5-(2-methylnaphthyl)pentyl, 6-(2-methylnaphthyl)hexyl, 3-methylnaphthyl, 3-methylnaphthylmethyl, 2-(3-methylnaphthyl)ethyl, 3-(3-methylnaphthyl)propyl, 4-(3-methylnaphthyl)butyl, 5-(3-methylnaphthyl)pentyl, 6-(3-methylnaphthyl)hexyl, 4-methylnaphthyl, 4-methylnaphthylmethyl, 2-(4-methylnaphthyl)ethyl, 3-(4-methylnaphthyl)propyl, 4-(4-methylnaphthyl)butyl, 5-(4-methylnaphthyl)pentyl, 6-(4-methylnaphthyl)hexyl, 2-propylnaphthyl, 2-propyl-5-naphthylmethyl, 2-(2-propylnaphthyl)ethyl, 3-(2-propylnaphthyl)propyl, 4-(2-propylnaphthyl)butyl, 5-(2-propylnaphthyl)pentyl, 6-(2-propylnaphthyl)hexyl, 3-propylnaphthyl, 3-propylnaphthylmethyl, 2-(3-propylnaphthyl)ethyl, 3-(3-propylnaphthyl)propyl, 4-(3-propylnaphthyl)butyl, 5-(3-propylnaphthyl)pentyl, 6-(3-propylnaphthyl)hexyl, 4-propylnaphthyl, 4-propylnaphthylmethyl, 2-(4-propylnaphthyl)ethyl, 3-(4-propylnaphthyl)propyl, 4-(4-propylnaphthyl)butyl, 5-(4-propylnaphthyl)pentyl, 6-(4-propylnaphthyl)hexyl, 2-cyclopentylnaphthyl, 2-cyclopentylnaphthylmethyl, 2-(2-cyclopentylnaphthyl)ethyl, 3-(2-cyclopentylnaphthyl)propyl, 4-(2-cyclopentylnaphthyl)butyl, 5-(2-cyclopentylnaphthyl)pentyl, 6-(2-cyclopentylnaphthyl)hexyl, 3-cyclopentylnaphthyl, 3-cyclopentylnaphthylmethyl, 2-(3-cyclopentylnaphthyl)ethyl, 3-(3-cyclopentylnaphthyl)propyl, 4-(3-cyclopentylnaphthyl)butyl, 5-(3-cyclopentylnaphthyl)pentyl, 6-(3-cyclopentylnaphthyl)hexyl, 4-cyclopentylnaphthyl, 4-cyclopentylnaphthylmethyl, 2-(4-cyclopentylnaphthyl)ethyl, 3-(4-cyclopentylnaphthyl)propyl, 4-(4-cyclopentylnaphthyl)butyl, 5-(4-cyclopentylnaphthyl)pentyl, 6-(4-cyclopentylnaphthyl)hexyl, 2-cyclohexylnaphthyl, 2-cyclohexylnaphthylmethyl, 2-(2-cyclohexylnaphthyl)ethyl, 3-(2-cyclohexylnaphthyl)propyl, 4-(2-cyclohexylnaphthyl)butyl, 5-(2-cyclohexylnaphthyl)pentyl, 6-(2-cyclohexylnaphthyl)hexyl, 3-cyclohexylnaphthyl, 3-cyclohexylnaphthylmethyl, 2-(3-cyclohexylnaphthyl)ethyl, 3-(3-cyclohexylnaphthyl)propyl, 4-(3-cyclohexylnaphthyl)butyl, 5-(3-cyclohexylnaphthyl)pentyl, 6-(3-cyclohexylnaphthyl)hexyl, 4-cyclohexylnaphthyl, 4-cyclohexylnaphthylmethyl, 2-(4-cyclohexylnaphthyl)ethyl, 3-(4-cyclohexylnaphthyl)propyl, 4-(4-cyclohexylnaphthyl)butyl, 5-(4-cyclohexylnaphthyl)pentyl, 6-(4-cyclohexylnaphthyl)hexyl, 2-phenyl-naphthyl, 2-phenyl-naphthylmethyl, 2-(2-phenyl-naphthyl)ethyl, 3-(2-phenyl-naphthyl)propyl, 4-(2-phenyl-naphthyl)butyl, 5-(2-phenyl-naphthyl)pentyl, 6-(2-phenyl-naphthyl)hexyl, 3-phenyl-naphthyl, 3-phenylnaphthylmethyl, 2-(3-phenyl-naphthyl)ethyl, 3-(3-phenyl-naphthyl)propyl, 4-(3-phenyl-naphthyl)butyl, 5-(3-phenyl-naphthyl)pentyl, 6-(3-phenyl-naphthyl)hexyl, 4-phenyl-naphthyl, 4-phenyl-naphthylmethyl, 2-(4-phenyl-naphthyl)ethyl, 3-(4-phenyl-naphthyl)propyl, 4-(4-phenyl-naphthyl)butyl, 5-(4-phenyl-naphthyl)pentyl, 6-(4-phenyl-naphthyl)hexyl, 2-phenoxy-naphthyl, 2-phenoxy-naphthylmethyl, 2-(2-phenoxy-naphthyl)ethyl, 3-(2-phenoxy-naphthyl)propyl, 4-(2-phenoxy-naphthyl)butyl, 5-(2-phenoxy-naphthyl)pentyl, 6-(2-phenoxy-naphthyl)hexyl, 3-phenoxy-naphthyl, 3-phenoxy-naphthylmethyl, 2-(3-phenoxy-naphthyl)ethyl, 3-(3-phenoxy-naphthyl)propyl, 4-(3-phenoxy-naphthyl)butyl, 5-(3-phenoxy-naphthyl)pentyl, 6-(3-phenoxy-naphthyl)hexyl, 4-phenoxy-naphthyl, 4-phenoxy-naphthylmethyl, 2-(4-phenoxy-naphthyl)ethyl, 3-(4-phenoxy-naphthyl)propyl, 4-(4-phenoxy-naphthyl)butyl, 5-(4-phenoxy-naphthyl)pentyl and 6-(4-phenoxy-naphthyl)hexyl groups; or C6-C16 substituted or non-substituted cycloalkyl group bound through C0-C6 methylene chain, such as cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, 2-methylcyclohexyl, 2-methylcyclohexylmethyl, 2-methylcyclohexylethyl, 2-methylcyclohexylpropyl, 2,2-dimethylcyclohexyl, 2,2-dimethylcyclohexylmethyl, 2-(2,2-dimethylcyclohexyl)ethyl, 2,3-dimethylcyclohexyl, 2,3-dimethylcyclohexylmethyl, 2-(2,3-dimethylcyclohexyl)ethyl, 3,3-dimethylcyclohexyl, 3,3-dimethylcyclohexylmethyl, 2-(3,3-dimethylcyclohexyl)ethyl, 2-cyclopentylcyclohexyl, 3-cyclopentyl-cyclohexyl, 4-cyclopentyl-cyclohexyl, 2-cyclohexylcyclohexyl, 3-cyclohexyl-cyclohexyl, 4-cyclohexyl-cyclohexyl, 2-phenyl-cyclohexyl, 3-phenyl-cyclohexyl, 4-phenyl-cyclohexyl, 2-phenoxy-cyclohexyl, 3-phenoxy-cyclohexyl, 4-phenoxy-cyclohexyl, 2-benzyl-cyclohexyl, 3-benzyl-cyclohexyl, 4-benzyl-cyclohexyl, 2-benzyloxy-cyclohexyl, 3-benzyloxy-cyclohexyl, 4-benzyloxy-cyclohexyl, 2-naphthyl-cyclohexyl, 3-naphthyl-cyclohexyl, 4-naphthyl-cyclohexyl, 4-naphthyl-cyclohexylmethyl, 2-(4-naphthyl-cyclohexyl)ethyl, 3-(4-naphthyl-cyclohexyl)propyl, 4-(4-naphthyl-cyclohexyl)butyl and 5-(4-naphthyl-cyclohexyl)pentyl, 6-(4-naphthyl-cyclohexyl)hexyl groups.
V represents carbon atom or nitrogen atom. R1 represents C1-C6 straight alkyl which is methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl group. R2 and R3 may or may not exist, may be the same or different, and each of which represents C1-C6 straight alkyl group which is methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl group; C1-C6 straight alkoxyl group which is methoxy, ethoxy, n-propyloxy, n-butyloxy, n-pentyloxy or n-hexyloxy group; C3-C8 branched alkyl group such as 1-methylethyl, 2-methylethyl, 1,1-dimethylethyl, 1,2-dimethylethyl, 2,2-dimethylethyl, 1-methylpropyl, 2-methylpropyl, 3-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3,3-dimethylpropyl, 1,2-dimethylpropyl, 1,3-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 2,4-dimethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylpentyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3;3-dimethylpentyl, 4,4-dimethylpentyl, 5,5-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 4,4-dimethylpentyl, 1,5-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,5-dimethylpentyl, 3,4-dimethylpentyl, 3,5-dimethylpentyl, 4,5-dimethylpentyl, 2,-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 5,5-dimethylhexyl, 6,6-dimethylhexyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 1,4-dimethylhexyl, 1,5-dimethylhexyl, 1,6-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,6-dimethylhexyl, 3,4-dimethylhexyl, 3,5-dimethylhexyl, 3,6-dimethylhexyl, 4,5-dimethylhexyl and 5,6-dimethylhexyl groups; C3-C8 branched alkoxyl group such as 2-methylethoxy, 2,2-dimethylethoxy, 2-methylpropyloxy, 3-methylpropyloxy, 2,2-dimethylpropyloxy, 3,3-dimethylpropyloxy, 2,3-dimethylpropyloxy, 2-methylbutyloxy, 3-methylbutyloxy, 4-methylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 4,4-dimethylbutyloxy, 2,3-dimethylbutyloxy, 2,4-dimethylbutyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 5-methylpentyloxy, 2,2-dimethylpentyloxy, 3,3-dimethylpentyloxy, 4,4-dimethylpentyloxy, 5,5-dimethylpentyloxy, 2,3-dimethylpentyloxy, 2,4-dimethylpentyloxy, 2,5-dimethylpentyloxy, 3,4-dimethylpentyloxy, 3,5-dimethylpentyloxy, 4,5-dimethylpentyloxy, 2-methylhexyloxy, 3-methylhexyloxy, 4-methylhexyloxy, 5-methylhexyloxy, 6-methylhexyloxy, 2,2-dimethylhexyloxy, 3,3-dimethylhexyloxy, 4,4-dimethylhexyloxy, 5,5-dimethylhexyloxy, 6,6-dimethylhexyloxy, 2,3-dimethylhexyloxy, 2,4-dimethylhexyloxy, 2,5-dimethylhexyloxy, 2,6-dimethylhexyloxy, 3,4-dimethylhexyloxy, 3,5-dimethylhexyloxy, 3,6-dimethylhexyloxy, 4,5-dimethylhexyloxy and 5,6-dimethylhexyloxy; hydroxyl group, chloro, bromo, fluoro, amino, C1-C6 monoalkylamino, dialkylamino in which each alkyl group has 2 to 6 carbon atoms, trifluoromethyl or nitro.
In cases where V and W are carbon atoms, and the bond between V and W is double bond, R4 does not exist, R5 is hydrogen; C1-C6 straight alkyl group which is 15 methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl group; C1-C6 straight alkoxyl group which is methoxy, ethoxy, n-propyloxy, n-butyloxy, n-pentyloxy or n-hexyloxy group; C3-C8 branched alkyl group such as 1-methylethyl, 2-methylethyl, 1,1-dimethylethyl, 1,2-dimethylethyl, 2,2-dimethylethyl, 1-methylpropyl, 2-methylpropyl, 3-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3,3-dimethylpropyl, 1,2-dimethylpropyl, 1,3-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 2,4-dimethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylpentyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 5,5-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,5-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,5-dimethylpentyl, 3,4-dimethylpentyl, 3,5-dimethylpentyl, 4,5-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 55-dimethylhexyl, 6,6-dimethylhexyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 1,4-dimethylhexyl, 1,5-dimethylhexyl, 1,6-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,6-dimethylhexyl, 3,4-dimethylhexyl, 3,5-dimethylhexyl, 3,6-dimethylhexyl, 4,5-dimethylhexyl and 5,6-dimethylhexyl groups; C3-C8 branched alkoxyl group such as 2-methylethoxy, 2,2-dimethylethoxy, 2-methylpropyloxy, 3-methylpropyloxy, 2,2-dimethylpropyloxy, 3,3-dimethylpropyloxy, 2,3-dimethylpropyloxy, 2-methylbutyloxy, 3-methylbutyloxy, 4-methylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 4,4-dimethylbutyloxy, 2,3-dimethylbutyloxy, 2,4-dimethylbutyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 5-methylpentyloxy, 2,2-dimethylpentyloxy, 3,3-dimethylpentyloxy, 4,4-dimethylpentyloxy, 5,5-dimethylpentyloxy, 2,3-dimethylpentyloxy, 2,4-dimethylpentyloxy, 2,5-dimethylpentyloxy, 3,4-dimethylpentyloxy, 3,5-dimethylpentyloxy, 4,5-dimethylpentyloxy, 2-methylhexyloxy, 3-methylhexyloxy, 4-methylhexyloxy, 5-methylhexyloxy, 6-methylhexyloxy, 2,2-dimethylhexyloxy, 3,3-dimethylhexyloxy, 4,4-dimethylhexyloxy, 5,5-dimethylhexyloxy, 6,6-dimethylhexyloxy, 2,3-dimethylhexyloxy, 2,4-dimethylhexyloxy, 2,5-dimethylhexyloxy, 2,6-dimethylhexyloxy, 3,4-dimethylhexyloxy, 3,5-dimethylhexyloxy, 3,6-dimethylhexyloxy, 4,5-dimethylhexyloxy and 5,6-dimethylhexyloxy groups; C6-C16 substituted or non-substituted phenyl group bound through C0-C6 methylene chain, such as phenyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, 2-methylphenyl, 2-methylbenzyl, 2-(2-methylphenyl)ethyl, 3-(2-methylphenyl)propyl, 4-(2-methylphenyl)butyl, 5-(2-methylphenyl)pentyl, 6-(2-methylphenyl)hexyl, 3-methylphenyl, 3-methylbenzyl, 2-(3-methylphenyl)ethyl, 4-(3-methylphenyl)propyl, 4-(3-methylphenyl)butyl, 5-(3-methylphenyl)pentyl, 6-(3-methylphenyl)hexyl, 4-methylphenyl, 4-methylbenzyl, 2-(4-methylphenyl)ethyl, 3-(4-methylphenyl)propyl, 4-(4-methylphenyl)butyl, 5-(4-methylphenyl)pentyl, 6-(4-methylphenyl)hexyl, 2-propylphenyl, 2-propylbenzyl, 2-(2-propylphenyl)ethyl, 3-(2-propylphenyl)propyl, 4-(2-propylphenyl)butyl, 5-(2-propylphenyl)pentyl, 6-(2-propylphenyl)hexyl, 3-propylphenyl, 3-propylbenzyl, 2-(3-propylphenyl)ethyl, 3-(3-propylphenyl)propyl, 4-(3-propylphenyl)butyl, 5-(3-propylphenyl)pentyl, 6-(3-propylphenyl)hexyl, 4-propylphenyl, 4-propylbenzyl, 2-(4-propylphenyl)ethyl, 3-(4-propylphenyl)propyl, 4-(4-propylphenyl)butyl, 5-(4-propylphenyl)pentyl, 6-(4-propylphenyl)hexyl, 2-cyclopentylphenyl, 2-cyclopentylbenzyl, 2-(2-cyclopentylphenyl)ethyl, 3-(2-cyclopentylphenyl)propyl, 4-(2-cyclopentylphenyl)butyl, 5-(2-cyclopentylphenyl)pentyl, 6-(2-cyclopentylphenyl)hexyl, 3-cyclopentylphenyl, 3-cyclopentylbenzyl, 2-(3-cyclopentylphenyl)ethyl, 3-(3-cyclopentylphenyl)propyl, 4-(3-cyclopentylphenyl)butyl, 5-(3-cyclopentylphenyl)pentyl, 6-(3-cyclopentylphenyl)hexyl, 4-cyclopentylphenyl, 4-cyclopentylbenzyl, 2-(4-cyclopentylphenyl)ethyl, 3-(4-cyclopentylphenyl)propyl, 4-(4-cyclopentylphenyl)butyl, 5-(4-cyclopentylphenyl)pentyl, 6-(4-cyclopentylphenyl)hexyl, 2-cyclohexylphenyl, 2-cyclohexylbenzyl, 2-(4-cyclohexylphenyl)ethyl, 3-(2-cyclohexylphenyl)propyl, 4-(2-cyclohexylphenyl)butyl, 5-(2-cyclohexylphenyl)pentyl, 6-(2-cyclohexylphenyl)hexyl, 3-cyclohexyl(phenyl, 3-cyclohexylbenzyl, 2-(3-cyclohexylphenyl)ethyl, 3-(3-cyclohexylphenyl)propyl, 4-(3-cyclohexylphenyl)butyl, 5-(3-cyclohexylphenyl)pentyl, 6-(3-cyclohexylphenyl)hexyl, 4-cyclohexylphenyl, 4-cyclohexylbenzyl, 2-(4-cyclohexylphenyl)ethyl, 3-(4-cyclohexylphenyl)propyl, 4-(4-cyclohexylphenyl)butyl, 5-(4-cyclohexylphenyl)pentyl, 6-(4-cyclohexylphenyl)hexyl, 2-phenyl-phenyl, 2-phenyl-benzyl, 2-(2-phenyl-phenyl)ethyl, 3-(2-phenyl-phenyl)propyl, 4-(2-phenyl-phenyl)butyl, 5-(2-phenyl-phenyl)pentyl, 6-(2-phenyl-phenyl)hexyl, 3-phenyl-phenyl, 3-phenyl-benzyl, 2-(3-phenyl-phenyl)ethyl, 3-(3-phenyl-phenyl)propyl, 4-(3-phenyl-phenyl)butyl, 5-(3-phenyl-phenyl)pentyl, 6-(3-phenyl-phenyl)hexyl, 4-phenyl-phenyl, 4-phenyl-benzyl, 2-(4-phenyl-phenyl)ethyl, 3-(4-phenyl-phenyl)propyl, 4-(4-phenyl-phenyl)butyl, 5-(4-phenyl-phenyl)pentyl, 6-(4-phenyl-phenyl)hexyl, 2-phenoxy-phenyl, 2-phenoxy-benzyl, 2-(2-phenoxy-phenyl)ethyl, 3-(2-phenoxy-phenyl)propyl, 4-(2-phenoxy-phenyl)butyl, 5-(2-phenoxy-phenyl)pentyl, 6-(2-phenoxy-phenyl)hexyl, 3-phenoxy-phenyl, 3-phenoxy-benzyl, 2-(3-phenoxy-phenyl)ethyl, 3-(3-phenoxy-phenyl)propyl, 4-(3-phenoxy-phenyl)butyl, 5-(3-phenoxy-phenyl)pentyl, 6-(3-phenoxy-phenyl)hexyl, 4-phenoxy-phenyl, 4-phenoxy-benzyl, 2-(4-phenoxy-phenyl)ethyl, 3-(4-phenoxy-phenyl)propyl, 4-(4-phenoxy-phenyl)butyl, 5-(4-phenoxy-phenyl)pentyl and 6-(4-phenoxy-phenyl)hexyl groups; C10-C16 substituted or non-substituted naphthyl group bound through C0-C6 methylene chain, such as naphthyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, 2-methylnaphthyl, 2-methylnaphthylmethyl, 2-(2-methylnaphthyl)ethyl, 3-(2-methylnaphthyl)propyl, 4-(2-methylnaphthyl)butyl, 5-(2-methylnaphthyl)pentyl, 6-(2-methylnaphthyl)hexyl, 3-methylnaphthyl, 3-methylnaphthylmethyl, 2-(3-methylnaphthyl)ethyl, 3-(3-methylnaphthyl)propyl, 4-(3-methylnaphthyl)butyl, 5-(3-methylnaphthyl)pentyl, 6-(3-methylnaphthyl)hexyl, 4-methylnaphthyl, 4-methylnaphthylmethyl, 2-(4-methylnaphthyl)ethyl, 3-(4-methylnaphthyl)propyl, 4-(4-methylnaphthyl)butyl, 5-(4-methylnaphthyl)pentyl, 6-(4-methylnaphthyl)hexyl, 2-propylnaphthyl, 2-propylnaphthylmethyl, 2-(2-propylnaphthyl)ethyl, 3-(2-propylnaphthyl)propyl, 4-(2-propylnaphthyl)butyl, 5-(2-propylnaphthyl)pentyl, 6-(2-propylnaphthyl)hexyl, 3-propylnaphthyl, 3-propylnaphthylmethyl, 2-(3-propylnaphthyl)ethyl, 3-(3-propylnaphthyl)propyl, 4-(3-propylnaphthyl)butyl, 5-(3-propylnaphthyl)pentyl, 6-(3-propylnaphthyl)hexyl, 4-propylnaphthyl, 4-propylnaphthylmethyl, 2-(4-propylnaphthyl)ethyl, 3-(4-propylnaphthyl)propyl, 4-(4-propylnaphthyl)butyl, 5-(4-propylnaphthyl)pentyl, 6-(4-propylnaphthyl)hexyl, 2-cyclopentylnaphthyl, 2-cyclopentylnaphthylmethyl, 2-(2-cyclopentylnaphthyl)ethyl, 3-(2-cyclopentylnaphthyl)propyl, 4-(2-cyclopentylnaphthyl)butyl, 5-(2-cyclopentylnaphthyl)pentyl, 6-(2-cyclopentylnaphthyl)hexyl, 3-cyclopentylnaphthyl, 3-cyclopentylnaphthylmethyl, 2-(3-cyclopentylnaphthyl)ethyl, 3-(3-cyclopentylnaphthyl)propyl, 4-(3-cyclopentylnaphthyl)butyl, 5-(3-cyclopentylnaphthyl)pentyl, 6-(3-cyclopentylnaphthyl)hexyl, 4-cyclopentylnaphthyl, 4-cyclopentylnaphthylmethyl, 2-(4-cyclopentylnaphthyl)ethyl, 3-(4-cyclopentylnaphthyl)propyl, 4-(4-cyclopentylnaphthyl)butyl, 5-(4-cyclopentylnaphthyl)pentyl, 6-(4-cyclopentylnaphthyl)hexyl, 2-cyclohexylnaphthyl, 2-cyclohexylnaphthylmethyl, 2-(2-cyclohexylnaphthyl)ethyl, 3-(2-cyclohexylnaphthyl)propyl, 4-(2-cyclohexylnaphthyl)butyl, 5-(2-cyclohexylnaphthyl)pentyl, 6-(2-cyclohexylnaphthyl)hexyl, 3-cyclohexylnaphthyl, 3-cyclohexylnaphthylmethyl, 2-(3-cyclohexylnaphthyl)ethyl, 3-(3-cyclohexylnaphthyl)propyl, 4-(3-cyclohexylnaphthyl)butyl, 5-(3-cyclohexylnaphthyl)pentyl, 6-(3-cyclohexylnaphthyl)hexyl, 4-cyclohexylnaphthyl, 4-cyclohexylnaphthylmethyl, 2-(4-cyclohexylnaphthyl)ethyl, 3-(4-cyclohexylnaphthyl)propyl, 4-(4-cyclohexylnaphthyl)butyl, 5-(4-cyclohexylnaphthyl)pentyl, 6-(4-cyclohexylnaphthyl)hexyl, 2-phenyl-naphthyl, 2-phenyl-naphthylmethyl, 2-(2-phenyl-naphthyl)ethyl, 3-(2-phenyl-naphthyl)propyl, 4-(2-phenyl-naphthyl)butyl, 5-(2-phenyl-naphthyl)pentyl, 6-(2-phenyl-naphthyl)hexyl, 3-phenyl-naphthyl, 3-phenylnaphthylmethyl, 2-(3-phenyl-naphthyl)ethyl, 3-(3-phenyl-naphthyl)propyl, 4-(3-phenyl-naphthyl)butyl, 5-(3-phenyl-naphthyl)pentyl, 6-(3-phenyl-naphthyl)hexyl, 4-phenyl-naphthyl, 4-phenyl-naphthylmethyl, 2-(4-phenyl-naphthyl)ethyl, 3-(4-phenyl-naphthyl)propyl, 4-(4-phenyl-naphthyl)butyl, 5-(4-phenyl-naphthyl)pentyl, 6-(4-phenyl-naphthyl)hexyl, 2-phenoxy-naphthyl, 2-phenoxy-naphthylmethyl, 2-(2-phenoxy-naphthyl)ethyl, 3-(2-phenoxy-naphthyl)propyl, 4-(2-phenoxy-naphthyl)butyl, 5-(2-phenoxy-naphthyl)pentyl, 6-(2-phenoxy-naphthyl)hexyl, 3-phenoxy-naphthyl, 3-phenoxy-naphthylmethyl, 2-(3-phenoxy-naphthyl)ethyl, 3-(3-phenoxy-naphthyl)propyl, 4-(3-phenoxy-naphthyl)butyl, 5-(3-phenoxy-naphthyl)pentyl, 6-(3-phenoxy-naphthyl)hexyl, 4-phenoxy-naphthyl, 4-phenoxy-naphthylmethyl, 2-(4-phenoxy-naphthyl)ethyl, 3-(4-phenoxy-naphthyl)propyl, 4-(4-phenoxy-naphthyl)butyl, 5-(4-phenoxy-naphthyl)pentyl and 6-(4-phenoxy-naphthyl)hexyl groups; or C6-C16 substituted or non-substituted cycloalkyl group bound through C0-C6 methylene chain, such as cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, 2-methylcyclohexyl, 2-methylcyclohexylmethyl, 2-methylcyclohexylethyl, 2-methylcyclohexylpropyl, 2,2-dimethylcyclohexyl, 2,2-dimethylcyclohexylmethyl, 2-(2,2-dimethylcyclohexyl)ethyl, 2,3-dimethylcyclohexyl, 2,3-dimethylcyclohexylmethyl, 2-(2,3-dimethylcyclohexyl)ethyl, 3,3-dimethylcyclohexyl, 3,3-dimethylcyclohexylmethyl, 2-(3,3-dimethylcyclohexyl)ethyl, 2-cyclopentyl-cyclohexyl, 3-cyclopentyl-cyclohexyl, 4-cyclopentyl-cyclohexyl, 2-cyclohexyl-cyclohexyl, 3-cyclohexyl-cyclohexyl, 4-cyclohexyl-cyclohexyl, 2-phenyl-cyclohexyl, 3-phenyl-cyclohexyl, 4-phenyl-cyclohexyl, 2-phenoxy-cyclohexyl, 3-phenoxy-cyclohexyl, 4-phenoxy-cyclohexyl, 2-benzylcyclohexyl, 3-benzyl-cyclohexyl, 4-benzyl-cyclohexyl, 2-benzyloxy-cyclohexyl, 3-benzyloxy-cyclohexyl, 4-benzyloxy-cyclohexyl, 2-naphthyl-cyclohexyl, 3-naphthyl-cyclohexyl, 4-naphthyl-cyclohexyl, 4-naphthyl-cyclohexylmethyl, 2-(4-naphthyl-cyclohexyl)ethyl, 3-(4-naphthyl-cyclohexyl)propyl, 4-(4-naphthyl-cyclohexyl)butyl, 5-(4-naphthyl-cyclohexyl)pentyl, and 6-(4-naphthyl-cyclohexyl)hexyl groups.
In cases where V is nitrogen atom, W is carbon atom and the bond between V and W is double bond, both R4 and R5 do not exist. In cases where V is carbon atom, W is nitrogen. atom or carbon atom, and the bond between V and W is single bond, R4 and R5 cooperatively represent carbonyl group.
The substituent(s) in the above-mentioned substituted phenyl group, substituted naphthyl group and substituted cycloalkyl group is(are) 1 to 5 C1-C6 straight alkyl group(s), C3-C6 branched alkyl group(s), phenyl group(s), phenoxy group(s), cyclopentyl group(s) or cyclohexyl group(s).
In the definition of each substituent, the expression that a group xe2x80x9cdoes not existxe2x80x9d or xe2x80x9cno groupxe2x80x9d means that the group is xe2x80x9cnot shown in the structural formulaxe2x80x9d, and includes both cases where the atom(s) does(do) not actually exist or hydrogen atom(s) exist(s). For example, in Formula I, in cases where Z1 does not exist, it means that Z1 bound to Y is not shown in the structural formula, so that it means that one or two hydrogen atoms are bound to Y. Similarly, for example, in Formula I, in cases where V and W are bound through double bond, R4 does not exist and hydrogen atom also does not exist. What is meant by this expression can be easily and clearly understood based on ordinary chemical knowledge.
Specific examples of the compounds according to the present invention include the following compounds:
2,4,5,7-tetraaza-7-(3-(4-indole-3-ylpiperidyl)propyl)-3-methyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(3-indole-3-ylpiperidyl)propyl)-3-methyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(2-(4-indole-3-ylpiperidyl)ethyl)3-methyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11,13-dichloro-7-(3-(4-indole-2-ylpiperidyl)propyl)-3-methyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11,13-difluoro-7-(3-(4-indole-2-ylpiperidyl)propyl)-3-methyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11,13-dihydroxy-7-(3-(4-indole-2-ylpiperidyl)propyl)-3-methyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11-(trifluoromethyl)-7-(3-(4-indole-2-ylpiperidyl)propyl)-3,13-methyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11,13-dichloro-7-(3-(4-indole-2-ylpiperidyl)propyl)-3-methyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
11-amino-2,4,5,7-tetraaza-12-bromo-dichloro-7-(3-(4-indole-2-ylpiperidyl)propyl)-3-methyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(4-indole-2-ylpiperidyl)propyl)-3-methyl-11-(methylethyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(4-indole-2-ylpiperidyl)propyl)-3,13-dimethyl-11-(methylethyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(4-indole-2-ylpiperidyl)propyl)-3,12-dimethyl-11-methoxytricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-12-bromo-7-(3-(4-indole-2-ylpiperidyl)propyl)-3-methyl-11-methoxytricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(4-indole-2-ylpiperidyl)propyl)-3,11,12-trimethyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(4-indole-2-ylpiperidyl)propyl)-3,11-dimethyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(4-indole-2-ylpiperidyl)propyl)-3,13-dimethyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-12ethyl-7-(3-(4-indole-2-ylpiperidyl)propyl)-3,11-dimethyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(4-indole-2-ylpiperidyl)propyl)-11-(dimethylamino)-3,12-dimethyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11-(ethylamino)-7-(3-(4-indole-2-ylpiperidyl)propyl)-3,13-dimethyltricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(4-diphenylmethylene)piperidyl)propyl)-3-trimethyl-11-methoxy-12-nitrotricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(3-(4-diphenylmethoxy)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(3-(4-((2-phenylphenyl)methyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(3-(4-cyclohexyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(3-(4-((3-phenoxyphenyl)methyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(3-(4-((4-phenoxyphenyl)methyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(3-(3-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-ethyl-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-propyl-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(i 0),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-11-methoxy-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-11,12-dimethoxy-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-11-chloro-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
6-hydroxy-3-(3-(4-(diphenylmethyl)piperazinyl)propyl-2-thioxohydroquinazoline-4-one,
2,4,5,7-tetraaza-3-methyl-11-hydroxy-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-11-isopropoxy-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-12-trifluoromethyl-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-11-dimethylamino-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(2-(4-diphenylmethyl)piperazinyl)ethyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(4-(4-diphenylmethyl)piperazinyl)butyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(4-(4-diphenylmethyl)piperidyl)butyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3,11,12-trimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3,11-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3,13-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-12-ethyl-3,11-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-11-(methylethyl)-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3,13-dimethyl-11-(methylethyl)-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3,12-dimethyl-11-methoxy-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-12-bromo-3-methyl-11-methoxy-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11,13-dibromo-3-methyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11-(trifluoromethyl)-3,13-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-11-methoxy-12-nitro-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
11-amino-2,4,5,7-tetraaza-12-bromo-3-methyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11,13-difluoro-3-methyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11,13-dihydroxy-3-methyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11-(dimethylamino)-3,12-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,7-tetraaza-11-(ethylamino)-3,13-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5-triaza-3-methyl-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,7,9(10),11-hexaene,
2,4,5-triaza-3-methyl-8-benzyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-3-methyl-8-(2-phenylethyl)-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-3,8,11-trimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-3,8,11,12-tetramethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-11-ethyl-3,8-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-3,8-dimethyl-1-(methylethyl)-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-3,8-dimethyl-11-methoxy-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-12-bromo-3,8-dimethyl-11-methoxy-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-11,13-dichloro-3,8-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7, 10,12-hexaene,
2,4,5-triaza-11,13-difluoro-3,8-dimethyl-7-(3-(4-diphenylmethyl)piperidinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7, 10,12-hexaene,
2,4,5-triaza-11-(trifluoromethyl)-3.8-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-3,8-dimethyl-11-methoxy-12-nitro-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5-triaza-12-bromo-3,8-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene-11-ylamine,
2,4,5-triaza-3,8-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene-11,13-diol,
2,4,5-triaza-3,8,12-trimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene-11-yl)dimethylamine,
(2,4,5-triaza-3,8,12-trimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene-11-yl)ethylamine,
2,4,5-triaza-11-(dimethylamino)-3,8-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene-13-ol,
(2,4,5-triaza-12-chloro-3,8-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene-11-yl)dimethylamine,
2,4,5,7-tetraaza-3-phenyl-7-(3-(4-diphenylmethyl)piperazyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-pentaene-8-one,
2,4,5,7-tetraaza-3-propyl-11-methoxy-7-(3-(4-diphenylmethyl)piperazinyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5,8-tetraaza-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene,
2,4,5,7-tetraaza-3-methyl-7-(2-((4-diphenylmethyl)piperidyl)methyl)phenyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-pentaene-8-one,
2,4,5,7-tetraaza-3-methyl-7-(3-(4-diphenylmethyl)piperidyl)phenyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-pentaene-8-one,
2,4,5,7-tetraaza-7-(1-ethyl-3-(4-diphenylmethyl)piperazinyl)propyl)-3-methyl tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-pentaene-8-one,
2,4,5,7-tetraaza-7-(3-(4-(3,4-dichlorobenzyl)piperazine-1-yl)propyl)-3-methyl tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(13),3,5,9(10),11-pentaene-8-one,
2,4,5-triaza-3,5-dimethyl-8-phenyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1,3,7,10,12-pentaene, and
2,4,5-triaza-3,8-dimethyl-7-(3-(4-diphenylmethyl)piperidyl)propyl)tricyclo[7.4.0.0 less than 2,6 greater than ]trideca-1(9),3,5,7,10,12-hexaene.
Processes for producing the compounds represented by Formula I (xe2x80x9cthe compounds represented by Formula Ixe2x80x9d, for example, will also be hereinafter referred to as simply xe2x80x9cFormula Ixe2x80x9d) will now be described, but the process for producing each compound is not restricted thereto. Further, in the various production processes, the reaction conditions may be appropriately selected from those described in the following.
Among the compounds represented by Formula I, those wherein V is carbon atom and the bond between W and V is single bond, and R4 and R5 cooperatively form carbonyl group, which are represented by Formula IV: 
(wherein W, X, Y, Z1, Z2, R1, R2 and R3 represent the same meanings as mentioned above)
may be produced by reacting Formula VI: 
(wherein A represents chloro, bromo, mesyl or tosyl group, W, X, R1, R2 and R3 represent the same meanings as mentioned above)
and Formula VII: 
(wherein Y, Z1 and Z2 represent the same meanings as mentioned above); or
may be produced by reacting Formula VIII: 
(wherein W, X, Y, Z1, Z2, R2 and R3 represent the same meanings as mentioned above)
with hydrazine and then with R1C(OR9)3 (wherein R1 represents the same meanings as mentioned above and R9 represents methyl, ethyl or propyl group).
Among the compounds represented by Formula VI, those wherein W is nitrogen atom, which are represented by Formula XIII, may be produced by the steps shown in the following. In the present specification, xe2x80x9cstepxe2x80x9d is indicated as xe2x80x9cstepxe2x80x9d in chemical reaction formulae. 
(wherein X, R1, R2, R3 and A represent the same meanings as mentioned above).
Step 1 is the step in which an isatoic anhydride IX is reacted with NHxe2x80x94Xxe2x80x94OH (wherein X represents the same meanings as mentioned above). This step may be carried out at 0xc2x0 C. to 50xc2x0 C., and sufficient reaction rate may be attained at room temperature. As the reaction solvent, an ether solvent such as tetrahydrofuran or dimethoxy ethane may usually be employed, but other solvents may also be employed. Although the reaction time may appropriately be selected depending on the reaction temperature and the like, it may usually be 1 to 24 hours.
Step 2 is the reaction for obtaining XI by reacting X with an excess amount of carbon disulfide in an alcoholic solvent such as methanol or ethanol. Usually, 2 to 4 equivalents of carbon disulfide is used, but more equivalents of carbon disulfide may be employed. The base used in this step may be sodium hydroxide, potassium hydroxide, pyridine, triethylamine or the like, but other bases may also be employed.
The reaction temperature may be 60 to 80xc2x0 C., but other temperatures may also be employed. Although the reaction time may be appropriately selected depending on the reaction temperature and the like, usually the reaction time may be about 2 to 96 hours.
Step 3 may be carried out by reacting the reaction product with hydrazine hydrate, and then with R1C(OR9)3. In cases where R1 in R1C(OR9)3 is methyl group, ortho triethyl acetate is usually employed as R1C(OR9)3, although R1C(OR9)3 is not restricted thereto. In the step of reacting the reaction product with hydrazine, although an alcoholic solvent such as methanol or ethanol is employed, non-polar solvents such as benzene, toluene and xylene, as well as polar solvents such as tetrahydrofuran and dimethylformamide may also be employed. The reaction proceeds also in the absence of a solvent. The reaction temperature may be room temperature to 200xc2x0 C., and usually about 100xc2x0 C. The mixing ratio of XI to hydrazine hydrate at the beginning of reaction may usually be about 1:10 to 1:100 by mole. Although the reaction time may appropriately be selected depending on the reaction temperature and the like, it may usually be 2 to 96 hours.
The next reaction wherein R1C(OR9)3 is used is carried out in an alcoholic solvent such as methanol or ethanol, or in the absence of solvent. The reaction may be carried out at 60xc2x0 C. to 150xc2x0 C., and preferably at 100xc2x0 C. to 120xc2x0 C. Although the mixing ratio of the reaction product of Step 1 to R1C(OR9)3 at the beginning of this second step is not restricted, usually about 1:2 to 1:30 by mole is preferred. Although the reaction time may appropriately be selected depending on the reaction temperature and the like, it may usually be about 1 to 8 hours.
Step 4 is the step for converting the hydroxyl group to chloro, bromo, tosyl or mesyl group. To convert the hydroxyl group to chloro, a chlorination reagent such as thionyl chloride, concentrated hydrochloric acid or carbon tetrachloride-triphenylphosphine may be employed, but other chlorination reagents may also be employed. To convert the hydroxyl group to bromo, a bromination reagent such as thionyl bromide, hydrobromic acid, carbon tetrabromide-triphenylphosphine may be employed, but other bromination reagents may also be employed. Conversion of the hydroxyl group to tosyl or mesyl group may be attained by reacting the reaction product with methanesulfonyl chloride or p-toluenesulfonyl chloride, respectively, in the presence of a base such as pyridine or triethylamine. The reaction may usually be carried out at xe2x88x9220xc2x0 C. to room temperature, and preferably be carried out under cooling in ice. As the solvent, although a halogen-containing solvent such as methylene chloride or chloroform is employed, pyridine or the like may also be employed. Although the mixing ratio of XII in the reaction mixture to the chlorination reagent, bromination reagent, sulfonyl chloride or the like at the beginning of the reaction is not restricted, it may usually be 1:1 to 1:5 by mole. Although the reaction time may appropriately be selected depending on the reaction temperature and the like, it may usually be about 1 to 24 hours.
XI may also be produced by the following steps: 
(wherein X, R2 and R3 represent the same meanings as mentioned above).
Step 1 is the step for condensing the o-nitrobenzoic acid derivative with H2Nxe2x80x94Xxe2x80x94OH (wherein X represents the same meanings as mentioned above). As the condensation reagent, those used for carrying out condensation between amino acids, such as DCC, BOP and PyBOP may usually be used, but the condensation reagent is not restricted thereto. As the reaction solvent, dimethylformamide, methylene chloride or the like is employed. The reaction may preferably be carried out under cooling in ice to at room temperature, but the reaction may also be carried out at other temperatures. The mixing ratio of XIV, H2Nxe2x80x94Xxe2x80x94OH and the condensation reagent at the beginning of the reaction is not restricted, but the mixing ratio of about 1:1:1 to 1:3:3 by mole is preferred. Although the reaction time may appropriately be selected depending on the reaction temperature and the like, it may usually be about 3 to 24 hours.
Step 2 is the step for reducing the nitro group to amino group. Usually, a hydrogenation method is employed, but other methods for reduction may also be employed. In case of hydrogenation reaction, usually, in an alcoholic solvent such as methanol or ethanol, a metal catalyst such as palladium/carbon, palladium hydroxide or platinum dioxide is employed, but other metal catalysts may also be employed. Although the reaction time may appropriately be selected depending on the reaction temperature and the like, it may usually be about 2 to 24 hours.
Step 3 is the step for reacting XVI with an excess amount of carbon disulfide in an alcoholic solvent such as methanol or ethanol. The base used in this step may be sodium hydroxide, potassium hydroxide, pyridine, triethylamine or the like. The reaction may be carried out between room temperature and 100xc2x0 C. and may preferably be carried out at 60xc2x0 C. to 80xc2x0 C. The mixing ratio of XVI, carbon disulfide and the base at the beginning of the reaction is not restricted, and usually about 1:3:1 to 1:10:3 by mole is preferred. Although the reaction time may appropriately be selected depending on the reaction temperature and the like, it may usually be about 2 to 96 hours.
Among the compounds represented by Formula VII, those wherein Y is carbon atom, Z2 does not exist, Z1 and Y are bonded through double bond, Z1 is represented by QCR6R7R8 wherein Q and R6 do not exist, and both R7 and R8 are phenyl groups, which are represented by Formula XX; and those wherein Y is carbon atom, Z2 does not exist, Z1 and Y are bonded through single bond, Z1 is represented by QCR6R7R8 wherein Q does not exist, R6 is hydrogen and both R7 and R8 are phenyl groups, which are represented by Formula XXII, may be produced by the following processes. 
(wherein R10 represents methyl or ethyl group, R11 represents acetyl, Boc or benzyl group).
Step 1 is the step for reacting XVII with a phenyl metal reagent. As the phenyl metal reagent, a Grignard reagent such as phenyl magnesium bromide; phenyl lithium or the like may be employed, but the phenyl metal reagent is not restricted thereto. The reaction may proceed at xe2x88x9220xc2x0 C. to 50xc2x0 C., and may preferably be carried out under cooling in ice to at room temperature. As the reaction solvent, an ether solvent such as tetrahydrofuran or dimethoxyethane may usually be employed. Although the mixing ratio of XVII to the phenyl metal reagent at the beginning of the reaction is not restricted, the mixing ratio of about 1:2 to 1:4 by mole is usually preferred. Although the reaction time may appropriately be selected depending on the reaction temperature and the like, it may usually be about 2 to 24 hours.
Step 2 may be carried out by heating the reaction mixture to reflux in acetic anhydride, or by treating the reaction mixture with a dilute mineral acid such as dilute hydrochloric acid or dilute sulfuric acid in an alcoholic solvent such as methanol or ethanol. Organic acids such as formic acid and acetic acid may also be employed. Although the mixing ratio of XVIII to the acid at the beginning of the reaction is not restricted, the mixing ratio of about 1:0.1 to 1:10 by mole is usually preferred. The reaction time may usually be about 5 to 24 hours.
Step 3 is the step for removing the protective group on the nitrogen atom. In cases where R11 is acetyl group, this step may be carried out by adding aqueous sodium hydroxide solution, aqueous potassium hydroxide solution or the like and heating the resultant to reflux in an alcoholic solvent such as methanol or ethanol. Although the mixing ratio of XIX to the base at the beginning of the reaction is not restricted, the mixing ratio of about 1:1 to 1:5 by mole is usually preferred. The reaction time may usually be about 5 to 20 hours.
In cases where R11 is Boc group, this step may be carried, out by treating the reaction mixture with an organic acid such as trifluoroacetic acid or with a dilute mineral acid such as dilute hydrochloric acid in a halogen-containing solvent such as chloroform or methylene chloride, thereby obtaining XX. This reaction may be carried out at xe2x88x9220xc2x0 C. to 50xc2x0 C., but usually carried out at room temperature. In this case, although the mixing ratio of XIX to the base at the beginning of the reaction is not restricted, the mixing ratio of about 1:0.1 to 1:10 by mole is usually preferred. The reaction time may usually be about 3 to 20 hours.
In cases where R11 is benzyl group, the benzyl group may be removed by treating the reaction mixture with sodium or lithium in liquid ammonia. In this case, although the mixing ratio of XIX to the alkaline metal at the beginning of the reaction is not restricted, the mixing ratio of about 1:1 to 1:5 by mole is usually preferred. The reaction time may usually be about 1 to 10 hours.
Step 4 may be carried out by hydrogenation by using a palladium-based catalyst such as palladium/carbon or palladium hydroxide, or a platinum-based catalyst such as platinum dioxide in an alcoholic solvent such as methanol or ethanol, or in a polar solvent such as ethyl acetate, tetrahydrofuran or dioxane. Although the reaction temperature is not restricted, usually about 10xc2x0 C. to 30xc2x0 C. is preferred. The reaction time may usually be about 3 to 48 hours. In cases where R11 is benzyl group, XXII may be directly obtained by Step 4.
Step 5 may be carried out similarly to Step 3.
Among the compounds represented by Formula VII, those wherein Y is carbon atom, Z1 does not exist, the bond between Z2 and the carbon atom is double bond, Z2 is QCR6R7R8 wherein Q and R6 do not exist, both R7 and R8 are phenyl groups, which are represented by Formula XXIII; and those wherein Y is carbon atom, Z1 does not exist, the bond between Z2 and the carbon atom is single bond, Z2 is QCR6R7R8 wherein Q does not exist, R6 is hydrogen, and both R7 and R8 are phenyl groups, which are represented by Formula XXI, may be produced in the similar manner to the production process of XX and XXII, using XXV as a starting material. 
(wherein R10 and R11 represent the same meanings as mentioned above).
Among the compounds re presented by Formula VII, those wherein Y is carbon atom, Z2 does not exist, the bond between Y and Z1 is single bond, Z1 is QCR6R7R8 wherein Q is oxygen atom, R6 is hydrogen, and both R7 and R8 are phenyl groups, which are represented by Formula XXVIII may be produced by the following process. 
(wherein R10 represents the same meanings as mentioned above).
Step 1 is the step for reacting diphenylmethoxy N-methylpiperidine XXVI with an alkyl chloroformate in a non-polar solvent such as benzene or toluene, thereby converting XXVI to XXVII. In this step, sufficient reaction rate may be obtained at 60xc2x0 C. to 80xc2x0 C., but the reaction may also be carried out at other temperatures. Although the mixing ratio of XXVI to the alkyl chloroformate at the beginning of the reaction is not restricted, a mixing ratio of about 1:1 to 1:3 by mole is usually preferred. The reaction time may appropriately be selected depending on the reaction temperature or the like, and may usually be about 10 to 24 hours.
Step 2 may be carried out by heating the reaction mixture to reflux under basic condition in an alcoholic solvent such as methanol or ethanol. As the base, aqueous sodium hydroxide solution or potassium hydroxide is preferred, but the base is not restricted to these. Although the mixing ratio of XXVII to the base at the beginning of the reaction is not restricted, a mixing ratio of about 1:2 to 1:5 by mole is usually preferred. The reaction time may usually be about 10 to 40 hours.
Among the compounds represented by Formula VII, those wherein Y is nitrogen atom, Z2 does not exist, the bond between Y and Z1 is single bond, Z1 is QCR6R7R8 wherein Q does not exist, R6 is hydrogen, and both R6 and R7 are hydrogen, which are represented by Formula XXXI, may be produced from a piperazine derivative XXIX and a substituted or non-substituted aldehyde. 
(wherein R8 and R11 represent the same meanings as mentioned above).
The condensation between the piperazine derivative XXIX and the substituted or non-substituted aldehyde may be carried out by azeotropic dehydration using Dean-Stark apparatus in a solvent such as benzene or toluene; or by using a Lewis acid such as trifluoroboron. In the latter case, although the reaction temperature is not restricted, usually about xe2x88x9220xc2x0 C. to 30xc2x0 C. is preferred. Although the mixing ratio of XXIX to the Lewis acid at the beginning of the reaction is not restricted, a mixing ratio of about 1:0.1 to 1:1 by mole is usually preferred. The reaction time may usually be about 1 to 10 hours. By reducing the reaction product with a reducing agent such as sodium borohydride in an alcoholic solvent such as methanol, XXX is obtained.
Alternatively, by treating a mixture of the piperazine derivative and the substituted or non-substituted aldehyde in an alcoholic solvent such as methanol with a reducing agent such as sodium triacetylboro hydride or sodium cyanoboro hydride, XXX may be obtained. In cases where sodium triacetylboro hydride, sodium cyanoboro hydride or the like is used as the reducing agent, the reaction may preferably be carried out at xe2x88x9220xc2x0 C. to room temperature, but the reaction may also be carried out at other temperatures. As the acid to be used in the reaction, acetic acid or hydrochloric acid may usually be used, but the acid is not restricted thereto. Although the mixing ratio of the piperazine derivative, substituted or non-substituted aldehyde, the reducing agent and the acid at the beginning of the reaction is not restricted, a mixing ratio of about 1:1:1:1 to 1:1:3:2 by mole is usually preferred.
Step 2 may be carried out in the similar manner to Step 3 in producing XX.
Among the compounds represented by Formula VII, those wherein Y is nitrogen atom, Z2 does not exist, the bond between Y and Z1 is single bond, Z1 is C6-C18 substituted or nion-substituted cyclohexyl may be produced in the similar manner to the process described above.
Among the compounds represented by Formula VIII, those wherein W is nitrogen atom, which are represented by Formula XXXIII, may be produced by the following process. 
(wherein X, Y, Z1, Z2, R2 and R3 represent the same meanings as mentioned above).
Step 1 is the step for condensing the isatoic anhydride IX with XXXIV represented by the formula below. As the reaction solvent, an ether solvent such as tetrahydrofuran or dimethoxyethane may usually be used, but other solvents may also be used. The reaction may be carried out at 0xc2x0 C. to 50xc2x0 C., and sufficient reaction rate may be obtained at room temperature. The mixing ratio of IX to XXXIV at the beginning of the reaction is not restricted, but usually about 1:1 to 1:2 by mole is preferred. The reaction time may be appropriately selected depending on the reaction temperature or the like, and usually about 1 to 24 hours. 
(wherein X, Y, Z1 and Z2 represent the same meanings as mentioned above).
Step 2 is the step for obtaining XXXIII by reacting XXXII with an excess amount of carbon disulfide in an alcoholic solvent such as methanol or ethanol. Carbon disulfide may usually be used in an amount of 2 to 4 equivalents, but more amounts of carbon disulfide may also be used. As the base, sodium hydroxide, potassium hydroxide, pyridine, triethylamine or the like may usually be employed, but other bases may also be employed. Although the mixing ratio of XXXII to the base at the beginning of the reaction is not restricted, usually about 1:1 to 1:3 by mole is preferred. The reaction time may be appropriately selected depending on the reaction temperature and the like, and usually about 2 to 96 hours.
Formula XXXIV may be produced by reacting NCxe2x80x94Xxe2x80x94A (wherein A represents the same meanings as mentioned above) with VII in the presence of a base, in a polar solvent such as acetonitrile or dimethylformamide at room temperature to 100xc2x0 C., preferably at 70xc2x0 C. to 80xc2x0 C., and then by reducing the cyano group. As the base, potassium carbonate or the like may usually be used, but other bases may also be used. Although the mixing ratio of NCxe2x80x94Xxe2x80x94A, VII and the base at the beginning of the reaction is not restricted, usually about 1:1:1 to 1:2:4 by mole is preferred. The reaction time may be appropriately selected depending on the reaction temperature and the like, and usually about 2 to 48 hours. Reduction of the cyano group may be carried out by using a reducing agent such as lithium aluminum hydride in an ether solvent such as tetrahydrofuran or dimethoxyethane; or by hydrogenation employing a metal catalyst such as palladium/carbon, palladium hydroxide or platinum dioxide; but other reduction conditions may also be employed.
The step for obtaining IV by reacting VI with VII may be carried out as follows. This step may be carried out by heating the reaction mixture in a polar solvent such as dimethylformamide, acetonitrile or dimethylsulfoxide to a temperature between 50xc2x0 C. and 100xc2x0 C. Although the mixing ratio of VI to VII at the beginning of the reaction is not restricted, usually about 1:1 to 1:3 by mole is preferred. The reaction time may be appropriately selected depending on the reaction temperature and the like, and usually about 2 to 24 hours.
The step for, reacting Formula VIII with hydrazine, and then with R1C(OR9)3 (wherein R1 represent the same meanings as mentioned above and R9 represents methyl, ethyl or propyl group) may be carried out in the similar manner to Step 3 in the production process of XIII.
Among the compounds represented by Formula I, those wherein W and V are carbon atoms, X is n-propyl group, R4 does not exist, R5 is hydrogen, C1-C6 straight alkyl group, C3-C8 branched alkyl group, C6-C22 substituted or non-substituted phenyl group, or C6-C22 substituted or non-substituted cycloalkyl group, and the bond between W and V is double bond, which are represented by Formula XXXV; and those wherein W and V are carbon atoms, X is n-propyl group, R4 is hydrogen, R5 is hydrogen, C1-C6 straight alkyl group, C3-C8 branched alkyl group, C6-C22 substituted or non-substituted phenyl group, or C6-C22 substituted or non-substituted cycloalkyl group, and the bond between W and V is single bond, which are represented by Formula XXXVI, may be produced by the following process. 
(wherein Y, Z1, Z2, R1, R2, R3 and R5 represent the same meanings as mentioned above) 
(wherein R2, R3, R5 and R10 represent the same meanings as mentioned above and R12 represents benzyl, tetrapyranyl, methoxymethyl, t-butyldiphenylsilyl, t-butyldimethylsilyl or triethylsilyl group.)
Step 1 is the step for obtaining XXXVIII by reacting XXXVII with glutaric anhydride in a non polar solvent such as benzene or toluene. The reaction is usually carried out under heating to reflux, but the reaction proceeds at other temperatures. Although the mixing ratio of XXXVII to glutaric anhydride at the beginning of the reaction is not restricted, usually about 1:1 to 1:2 by mole is preferred. The reaction time may usually be about 4 to 12 hours.
Step 2 may be carried out by heating the reaction mixture in aqueous potassium hydroxide solution or aqueous sodium hydroxide solution to reflux to obtain a cyclized compound, and then heating the product to reflux under acidic condition attained by hydrochloric acid, sulfuric acid or the like, in methanol or ethanol. As the base used in the first step, usually aqueous potassium hydroxide solution or aqueous sodium hydroxide solution is used, but other bases such as potassium t-butoxide in an ether solvent such as tetrahydrofuran or dimethoxyethane may also be used. The mixing ratio of XXXVIII to the base at the beginning of the first step of the reaction is not restricted, but usually about 1:1 to 1:5 by mole is preferred. The reaction time may usually be about 4 to 12 hours. The reaction time of the second step may usually be about 3 to 8 hours.
Step 3 is the step for reducing the ester group. As the reducing agent, lithium aluminum hydride, diisobutyl aluminum hydride or the like may be employed, but other reducing agents may also be employed. As the reaction solvent, an ether solvent such as tetrahydrofuran or dimethoxyethane may be used. The reaction temperature is not restricted, but usually about xe2x88x9210xc2x0 C. to 30xc2x0 C. is appropriate. Although the mixing ratio of XXXIX to the reducing agent is not restricted, usually about 1:1 to 1:3 by mole is appropriate. The reaction time may usually be about 2 to 6 hours.
Step 4 is the step for protecting the alcohol. In cases where R12 is t-butyldiphenylsilyl, the step may usually be carried out by reacting the reaction product with t-butyldiphenylsilyl chloride using imidazole as a base in dimethylformamide. In cases where R12 is t-butyldimethylsilyl group, usually, t-butyldimethylsilyl chloride is reacted with the reaction product using imidazole, morpholine or the like as a base in a polar solvent such as dimethylformamide or tetrahydrofuran. In cases where R14 is trimethylsilyl group, the step may usually be carried out by reacting trimethylsilyl chloride with the reaction product using pyridine as a base in a halogen-containing solvent such as methylene chloride, but other methods may also be employed. In cases where R12 is benzyl group, the step may usually be carried out by reacting benzyl bromide with the reaction product using a base such as sodium hydride or potassium t-butoxide in an ether solvent such as tetrahydrofuran or dimethoxyethane, but other methods may also be employed. In cases where R12 is tetrahydropyranyl group, the step may be carried out by reacting dihydropyran with the reaction product under acidic condition, in a halogen-containing solvent such as methylene chloride. As the acid, p-toluenesulfonic acid is usually employed, but the acid is not restricted thereto. In cases where R12 is methoxymethyl group, the step may be carried out by reacting chloromethylmethyl ether with the reaction product using diisopropylethylamine as a base in a halogen-containing solvent such as methylene chloride, but other methods may also be employed. In these cases, the reaction temperature is not restricted but usually about 0xc2x0 C. to 30xc2x0 C. is appropriate. Although the mixing ratio of XXXX to the base or the acid at the beginning of the reaction is not restricted, usually about 1:1 to 1:3 by mole is appropriate. The reaction time may appropriately be selected depending on the reaction temperature and the like, and usually about 1 to 24 hours.
Step 5 is the step for obtaining XXXXII by reacting XXXXI with an excess amount of diphosphorus pentasulfide or Lawesson""s reagent. Diphosphorus pentasulfide or Lawesson""s reagent may be used in an amount of 1 to 4 equivalents, but larger amounts may also be employed. In cases where diphosphorus pentasulfide is used, in an ether solvent such as tetrahydrofuran or dimethoxyethane, a base such as pyridine, triethylamine or sodium hydrogen carbonate may be used, but other bases may also be employed. The reaction may be carried out at 50xc2x0 C. to 100xc2x0 C., but the reaction may be carried out at other temperatures. In cases where Lawesson""s reagent is used, XXXXII may be obtained at room temperature to 100xc2x0 C. in a non-polar solvent such as toluene or in an ether solvent such as dimethoxyethane. Although the reaction time may be appropriately selected depending on the reaction temperature and the like, in case of using diphosphorus pentasulfide, the reaction time may usually be about 20 to 200 hours, and in case of using Lawesson""s reagent, the reaction time may usually be about 2 to 10 hours.
Step 6 may be carried out by reacting the reaction product with hydrazine hydrate and then with R1C(OR9)3. In cases where R1 in R1C(OR9)3 is methyl group, ortho triethyl acetate is usually used, but not restricted thereto. In this step, in the step of the reaction with hydrazine, an alcoholic solvent such as methanol or ethanol is usually used, but a non-polar solvent such as benzene, toluene or xylene, or a polar solvent such as tetrahydrofuran or dimethylformamide may also be employed. The reaction proceeds also in the absence of a solvent. The reaction temperature may be room temperature to 200xc2x0 C., and usually about 100xc2x0 C. Although the mixing ratio of XXXXII to the hydrazine hydrate at the beginning of the reaction is not restricted, usually about 1:10 to 1:100 is appropriate. The reaction time may be appropriately selected depending on the reaction temperature and the like, but the reaction time may usually be about 1 to 8 hours.
Step 7 is the step for removing the protective group of the hydroxyl group. In cases where R12 is diphenylmethylsilyl, t-butyldimethylsilyl or trimethylsilyl group, the step may usually be carried out by reacting tetra n-butylammonium fluoride with the reaction product in a polar solvent such as dimethylformamide at room temperature, or by treating the reaction mixture with acetic acid in a mixed solvent such as tetrahydrofuran-water at room temperature to 60xc2x0 C. Other reaction conditions may also be employed. In the former case, although the mixing ratio of XXXXIII to tetra n-butylammonium fluoride at the beginning of the reaction is not restricted, usually about 1:1 to 1:3 is appropriate. The reaction time may appropriately be selected depending on the reaction temperature and the like, and may usually be about 2 to 12 hours. In the latter case, although the mixing ratio of XXXXIII to acetic acid at the beginning of the reaction is not restricted, usually about 1:0.1 to 1:3 by mole is appropriate. The reaction time may appropriately be selected depending on the reaction temperature and the like, and may usually be about 1 to 10 hours.
In cases where R12 is benzyl group, the step may usually. be carried out by hydrogenation by using a palladium-based catalyst such as palladium/carbon or palladium hydroxide, or using a platinum-based catalyst such as platinum dioxide in an alcoholic solvent such as methanol or ethanol, or in a polar solvent such as ethyl acetate, tetrahydrofuran or dioxane, but other methods may also be employed. Although the reaction temperature is not restricted, usually about 10xc2x0 C. to 30xc2x0 C. is appropriate. The reaction time may appropriately be selected depending on the reaction temperature and the like, and may usually be about 2 to 12 hours.
In cases where R12 is tetrahydropyranyl group, the step may be carried out by treating the reaction mixture with a dilute mineral acid such as dilute hydrochloric acid or dilute sulfuric acid, or with an organic acid such as p-toluenesulfonic acid, in an alcoholic solvent such as methanol or ethanol, or in tetrahydrofuran, dimethoxyethane, dioxane or the like. The reaction may preferably be carried out under cooling in ice to at room temperature, but .the reaction temperature is not restricted thereto. Although the mixing ratio of XXXXIII to the organic acid at the beginning of the reaction is not restricted, usually about 1:0.1 to 1:1 by mole is appropriate. The reaction time may appropriately be selected depending on the reaction temperature and the like, and may usually be about 1 to 10 hours.
In cases where R12 is methoxymethyl group, the step may be carried out by adding a dilute mineral acid such as dilute hydrochloric acid or dilute-sulfuric acid, or an organic acid such as p-toluenesulfonic acid and then heating the reaction mixture in a solvent such as methanol. The reaction temperature is not restricted, but usually about 10xc2x0 C. to 60xc2x0 C. is appropriate. Although the mixing ratio of XXXXIII to the organic acid at the beginning of the reaction is not restricted, usually about 1:0.1 to 1:10 by mole is appropriate. The reaction time may appropriately be selected depending on the reaction temperature and the like, and may usually be about 1 to 10 hours.
Step 8 is the step for converting the hydroxyl group to chloro, bromo, tosyl or mesyl group. To convert the hydroxyl group into chloro, a chlorination reagent such as thionyl chloride, concentrated hydrochloric acid or carbon tetrachloride-triphenylphosphine may be used, but other chlorination agents may also be employed. To convert the hydroxyl group into bromo, a bromination reagent such as thionyl bromide, hydrobromic acid or carbon tetrabromide-triphenylphosphine may be used, but other bromination agents may also be employed. To convert the hydroxyl group into tosyl or mesyl group, the reaction product is reacted with methanesulfonyl chloride or p-toluenesulfonyl chloride, respectively, in the presence of a base such as pyridine or triethylamine. This step may usually be carried out at xe2x88x9220xc2x0 C. to room temperature, and preferably carried out under cooling in ice. As the solvent, a halogen-containing solvent such as methylene chloride or chloroform may be employed, but pyridine or the like may also be employed. Although the mixing ratio of XXXXIV to the chlorination agent, bromination agent or the reagent such as sulfonyl chloride or the like at the beginning of the reaction is not restricted, usually about 1:1 to 1:3 by mole is appropriate. The reaction time may appropriately be selected depending on the reaction temperature and the like, and may usually be about 2 to 30 hours.
Step 9 is the step for reacting XXXXV with VII at room temperature to 100xc2x0 C., preferably at 70xc2x0 C. to 80xc2x0 C. in a polar solvent such as acetonitrile or dimethylformamide in the presence of a base. As the base, potassium carbonate is usually employed, but other bases may also be employed. Although the mixing ratio of XXXXV to VII at the beginning of the reaction is not restricted, usually about 1:1 to 1:2 by mole is appropriate. The reaction time may appropriately be selected depending on the reaction temperature and the like, and may usually be about 2 to 48 hours.
Step 10 is the step for reducing the double bond. The step may usually be carried out by hydrogenation by using a palladium-based catalyst such as palladium/carbon or palladium hydroxide, or using a platinum-based catalyst such as platinum dioxide, in an alcoholic solvent such as methanol or ethanol, or in a polar solvent such as ethyl acetate, tetrahydrofuran or dioxane, but other methods may also be employed. The reaction temperature is not restricted, and usually about 10xc2x0 C. to 30xc2x0 C. is appropriate. The reaction time may appropriately be selected depending on the reaction temperature and the like, and may usually be about 2 to 40 hours.
In cases where the novel triazolo derivative according to the present invention contains one or more asymmetric carbon atoms, racemic compounds, diastereomers and each of the optical isomers could exist, and any of these may be used in the present invention.
Examples of pharmaceutically acceptable salts of the compounds represented by Formula I include inorganic acid salts such as hydrochloric acid salt, hydrobromic acid salt, sulfuric acid salt, boric acid salt and phosphoric acid salt; organic acid salts such as maleic acid salt, fumaric acid salt, tartaric acid salt, succinic acid salt, malic acid salt, lactic acid salt, citric acid salt, malonic acid salt, benzoic acid salt, paratoluenesulfonic acid salt and methanesulfonic acid salt; and acid addition salts such as lysine, glycine, phenylalanine, asparagine and glutamine-added salts.
The triazolo derivatives represented by Formula I and pharmaceutically acceptable salts thereof may be used for therapy of various diseases utilizing inhibition of the actions of chemokines mediated through chemokine receptors such as CCR1, CCR2 and CCR3, especially, the actions of CC chemokines. For example, the triazolo derivatives represented by Formula I and pharmaceutically acceptable salts thereof are useful as therapeutic agents for allergic diseases such as bronchial asthma and atopic dermatitis; inflammatory diseases such as chronic rheumatoid arthritis; and for autoimmune diseases such as nephritis and ulcerative colitis; and as anti-AIDS drugs. They are also useful for prophylaxis and therapy of various diseases other than those mentioned above, in which chemokines are thought to participate.
The compounds represented by Formula I and acid addition salts thereof may be administered orally or parenterally (e.g., percutaneous, intravenous or rectal administration) as they are in the form of powder or as medical compositions in appropriate formulations to mammals. Examples of the formulations for administration include tablets, powders, balls, capsules, granules, syrups, liquids, injection solutions, emulsions, suspensions and suppositories. These formulations may be prepared by known methods, and include various carriers which are conventionally used in the field of formulation of medicines. Examples of these carriers include, for solid formulations, vehicles, lubricants, binders and disintegrators; for liquid formulations, solvents, solubilizers, suspending agents and soothing agents. Additives such as preservatives, antioxidants, coloring agents, sweetners, adsorbing agents and wetting agents may be used.
Examples of the vehicles include lactose, saccharose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose and light anhydrous silicic acid. Examples of the lubricants include magnesium stearate, calcium stearate, talc and colloidal silica. Examples of the binders include crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxyprqpyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose and sodium carboxymethyl cellulose. Examples of the disintegrators include starch, carboxymethyl cellulose, potassium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch and L-hydroxypropyl cellulose. Examples of the solvents include water for injection, alcohol, propylene glycol, Macrogol, sesame oil and corn oil. Examples of the solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Examples of the suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate; and hydrophilic macromolecules such as polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Examples of the isotonic agents include glucose, sodium chloride, D-sorbitol and D-mannitol. Examples of the buffering agents include phosphoric acid salts, acetic acid salts, carbonic acid salts and citric acid salts. Examples of the soothing agents include benzyl alcohol. Examples of the antiseptics include paraoxy benzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid. Examples of the antioxidants include sulfurous acid salts and ascorbic acid.
The effective dose and the number of administration of the compound of Formula I or the pharmaceutically acceptable salt thereof vary depending on the formulation, and age, body weight, state or severity of the symptom of the patient, but usually 0.1 to 1000 mg, preferably 1 to 200 mg of the compound or the salt thereof may be administered to an adult per day in one time or in several times.
Unless undesirable interactions with the compound of Formula I or the pharmaceutically acceptable salt thereof occur, the formulation may include one or more of other therapeutically effective components. Examples of such therapeutic components include steroid drugs, nonsteroidal anti-inflammatory drugs, lipoxygenase inhibitors, leucotriene antagonists, bronchodilators, thromboxane synthesis inhibitors, thromboxane antagonists, histamine antagonists, histamine liberation inhibitors, platelet activating factor (PAF) antagonists, serotonin antagonists, adenosine receptor antagonists, adrenergic xcex2-receptor antagonists, immunosuppressive agents and immunomodulators.